This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The central hypothesis of this proposal is: Retroviral-mediated transfer of a normal human ADA cDNA into CD34+ hematopoietic stem cells of infants and children with ADA-deficient SCID, who have undergone marrow cytoreduction and are not on PEG-ADA replacement, can be performed safely and will result in the production of mature T lymphocytes, expressing ADA enzyme activity and restoring immune function. In all, these clinical studies will determine the safety and effectiveness of current retroviral-mediated gene transfer techniques to introduce genes into human hematopoietic stem cells from the bone marrow. Two different retroviral vectors, GCsap-M-ADA and MND-ADA, will be compared for their abilities to express the human ADA cDNA and confer a selective survival advantage upon T lymphocytes. Marrow cytoreduction in the absence of PEG-ADA will be tested, to assess the safety of the approach and its effect on engraftment and selective survival of gene-corrected cells. Additionally, the specific benefits for reconstitution of immunity in ADA-deficient SCID patients will be assessed.